8-Mercaptoguanine-based inhibitors of Mycobacterium tuberculosis dihydroneopterin aldolase: synthesis,in vitro inhibition and docking studies

The dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of FolB protein is required for the conversion of 7,8-dihydroneopterin (DHNP) to 6-hydroxymethyl-7,8-dihydropterin (HP) and glycolaldehyde (GA) in the folate pathway. FolB protein from Mycobacterium tuberculosis (MtFolB) is essential for bacilli survival and represents an important molecular target for drug development. S8-functionalized 8-mercaptoguanine derivatives were synthesised and evaluated for inhibitory activity against MtFolB. The compounds showed IC₅₀ values in the submicromolar range. The inhibition mode and inhibition constants were determined for compounds that exhibited the strongest inhibition. Additionally, molecular docking analyses were performed to suggest enzyme-inhibitor interactions and ligand conformations. To the best of our knowledge, this study describes the first class of MtFolB inhibitors.     

Reproductive biology and population structure of white warehou Seriolella caerulea and silver warehou Seriolella punctata in the austral zone off Chile

Using an extensive database compiled by scientific observers aboard commercial fishing operations between 1984 and 2014, we describe the maturity and size structures of white warehou Seriolella caerulea and silver warehou Seriolella punctata from by-catch of the trawling industrial fisheries operating in the austral zone off Chile. Macroscopic maturity stages and gonadosomatic (I_GS) index show mature females throughout the year and a pronounced spawning period in both austral autumn and winter seasons, with an I_GS peak in July for S. punctata and August for S. caerulea. Reproductive patterns in both species show an extended spawning season (July to September) across the area between 43 and 47° S. Length–mass relationships showed significant differences between sexes in both species, where females reach a larger size. Fork length at 50% maturity was 43.5 cm for S. caerulea and 37.2 cm for S. punctata. Female catch composition is dominated by adult fish (96% for S. caerulea and 86% for S. punctata). Currently, both species are exploited with no assessment and management-decision framework. Therefore, information regarding reproductive biology and demographic traits becomes an important baseline to ensure adequate fisheries management for both species.     

Creatine nanoliposome reverts the HPA-induced damage in complex II–III activity of the rats’ cerebral cortex

Molecular Biology Reports - Phenylketonuria (PKU) is a metabolic disorder accumulating phenylalanine (Phe) and its metabolites in plasma and tissues of the patients. Regardless of the mechanisms,...     

Dung beetle diversity and functions suggest no major impacts of cattle grazing in the Brazilian Pantanal wetlands

1. Dung beetles perform relevant ecological functions in pastures, such as dung removal and parasite control. Livestock farming is the main economic activity in the Brazilian Pantanal. However, the impact of cattle grazing on the Pantanal's native dung beetle community, and functions performed by them, is still unknown. 2. This study evaluated the effects of cattle activity on dung beetle community attributes (richness, abundance, biomass, composition, and functional group) as well as their ecological functions (dung removal and soil bioturbation) in the Pantanal. In January/February 2016, dung beetles were sampled and their ecological functions measured in 16 sites of native grasslands in Aquidauana, Mato Grosso do Sul, Brazil, 10 areas regularly grazed by cattle and six control ungrazed areas (> 20 years of abandonment). 3. In all, 1169 individuals from 30 species of dung beetles were collected. Although abundance, species richness, and biomass did not differ between grasslands with and without cattle activity, species composition and functional groups differed among systems. Large roller beetles were absent from non‐cattle grasslands, and the abundance, richness, and biomass of medium roller beetles was higher in those systems. 4. Despite causing changes in species/functional group composition, the results of this study show that a density compensation of functional groups in cattle‐grazed natural grasslands seems to have conserved the ecological functions (dung removal and soil bioturbation), with no significant differences between systems. 5. Therefore, these results provide evidence that cattle breeding in natural grasslands of the Brazilian Pantanal can integrate livestock production with the conservation of the dung beetle community and its ecological functions.     

Different domains are critical for oligomerization compatibility of different connexins

Oligomerization of connexins is a critical step in gap junction channel formation. Some members of the connexin family can oligomerize with other members and form functional heteromeric hemichannels [e.g. Cx43 (connexin 43) and Cx45], but others are incompatible (e.g. Cx43 and Cx26). To find connexin domains important for oligomerization, we constructed chimaeras between Cx43 and Cx26 and studied their ability to oligomerize with wild-type Cx43, Cx45 or Cx26. HeLa cells co-expressing Cx43, Cx45 or Cx26 and individual chimaeric constructs were analysed for interactions between the chimaeras and the wild-type connexins using cell biological (subcellular localization by immunofluorescence), functional (intercellular diffusion of microinjected Lucifer yellow) and biochemical (sedimentation velocity through sucrose gradients) assays. All of the chimaeras containing the third transmembrane domain of Cx43 interacted with wild-type Cx43 on the basis of co-localization, dominant-negative inhibition of intercellular communication, and altered sedimentation velocity. The same chimaeras also interacted with co-expressed Cx45. In contrast, immunofluorescence and intracellular diffusion of tracer suggested that other domains influenced oligomerization compatibility when chimaeras were co-expressed with Cx26. Taken together, these results suggest that amino acids in the third transmembrane domain are critical for oligomerization with Cx43 and Cx45. However, motifs in different domains may determine oligomerization compatibility in members of different connexin subfamilies.     

Effects of hybridization on sea turtle fitness

Sea turtle hybridization is a common phenomenon in Brazil between loggerheads (Caretta caretta) and hawksbills (Eretmochelys imbricata) as well as between loggerheads and olive ridleys (Lepidochelys olivacea). In a previous study we showed that the reproductive output of loggerhead/hawksbill hybrids is similar to that of parental species, suggesting no negative effect of hybridization at this life stage. In this study, we used pooled amplicon sequencing to assign species identity to dams and their progeny, and to investigate the fitness consequences of hybridization, using hatchling viability as a proxy for fitness. We genotyped 4829 hatchlings from egg clutches laid by 78 loggerheads, 13 hawksbills, seven loggerhead/hawksbill hybrids, and three loggerhead/olive ridley hybrids. The proportion of viable hybrid (heterozygous) hatchlings was similar to that of homozygous hatchlings (based on data at two loci), independent of the dam’s genotype. Multiple species paternity was observed in 35.7% of the nests. Both hybrid males and females were fertile and produced viable offspring, and we found no evidence for hybrid breakdown. We suggest a genome-wide study of the hybrids and parental species to better characterize hybrids, as well as studies on additional demographic and ecological parameters to further assess the effects of hybridization and its consequences for sea turtles and their environment.     

Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.